New synthetic methods for functionalized carbocyclic compounds were developed on the basis of [3 + 2] and [5 + 2] cycloaddition reactions by using carbocation species. Under the influence of a Lewis acid, 3- (methylthio) -2-siloxyallyl acetates reacted with various kinds of olefins to afford the corresponding cyclopentanones in good yields. The sterically more hindered regioisomer was predominantly formed in every case, and surprisingly high stereoselectivity was also observed in certain cases. An efficient synthetic method for (-) -coriolin has been developed on the basis of the [3 + 2] cycloaddition reaction. On the other hand, 5-acetoxy-2- [(trimethylsilyl) methyl] -1-penten-3-yne-dicobalthexacarbonyl underwent [5 + 2] cycloaddition reactions with enol triisopropylsill ethers to give seven-membered compounds. The reactions with cyclic enol silyl ethers as well as acyclic enol silyl ethers exhibited remarkably high diastereoselectivity.
Selected recent examples of enantioselective radical-mediated reactions of carbonyl compounds by use of organotin reagents are reviewed. Enantioselective reduction, allylations and cyclizations of α-halocarbonyl compounds promoted by chiral Lewis acids have met with success. Employment of chiral organotin hydrides has been also successful in yielding optically active compounds. Furthermore, hydrogen atoms and allyl groups can be transferred enantioselectively to radicals undergoing additions to α, β-unsaturated carbonyl compounds in the presence of chiral Lewis acids. β-Enantioselective radical additions catalyzed by chiral Lewis acids can be achieved. In addition, there are some cases where external achiral ligands show remarkable effects on asym-metric induction.
Malaria is the world's most important tropical parasitic disease and there are an estimated 300-500 million cases of malaria each year. The emergence of multi-drug resistant strains of the parasite is exacerbating the situation. Febrifugine, which was isolated from Dichroa febrifuga and Hydrangea umbellata along with isofebrifugine, is a well-known candidate of antimalarial agent. The plane structure of febrifugine and isofebrifugine was first proposed in 1950. Subsequently, their relative and absolute structures were proposed, based on Baker's synthetic work. The relative configuration of febrifugine was corrected in 1973 and then the absolute structures of febrifugine and isofebrifugine were corrected in 1999. These repeated errors and corrections have caused much confusion in the study of the relationship between the structure and antimalarial activity of febrifugine derivatives. However, investigation of the antimalarial activity of febrifugine derivatives is beginning anew, since it was reported that febrifugine had higher activity than clinically used antimalarial drugs, and a derivative more potent than febrifugine was found.
A nickel-promoted intramolecular cyclization of 1, 3-diene with the tethered carbonyl group was developed using the catalyst generated by reduction of Ni(acac)2 with DIBAL-H in the presence of PPh3. The reaction course of this cyclization can be accounted for by two possible mechanisms. In one mechanism, a nickel hydride complex plays a key role and the cyclization proceeds via πallylnickel intermediate. In the other mechanism, a zerovalent nickel complex is the active species and the cyclization proceeds via the nickelacycle intermediate. These mechanistic considerations led to find two nickel (0) -catalyzed cyclizations of 1, 3-diene and the tethered aldehyde, in which the five- to seven-membered ring products were produced in a regio- and stereoselective manner via, π-allylnickel intermediate (Type I cyclization) or via transmetalation process of nickelacycle intermediate with iBu2Al-acac (Type II cyclization). We also succeeded in applying these cyclizations to the syntheses of (-) -elaeokanine C and (+)-prostaglandin F2α, and in demonstrating the catalytic asymmetric cyclization using Type I cyclization.
We developed a regio- and stereoselective method for introducing 1-hydroxyethyl, 2-hydroxyethyl, and vinyl groups at the position β to a hydroxyl group in halohydrins or α-phenylselenoalkanols using an intramolecular radical cyclization reaction with a dimethyl- or diphenylvinylsilyl group as a temporary connecting radical-acceptor tether (Scheme 14). Thus, when a vinylsilyl ether of halohydrins or α-phenylselenoalkanols (A) was subjected to the radical reaction with Bu3SnH/AIBN, the selective introduction of both 1-hydroxyethyl and 2-hydroxyethyl groups can be achieved, depending on the concentration of Bu3SnH in the reaction system, via a 5-exo-cyclization intermediate E or a 6-endo-cyclization intermediate F, respectively, after oxidative ring-cleavage by treating the cyclization products under Tamao oxidation conditions. A vinyl group can also be introduced by photo-irradiating the vinylsilyl ether A in the presence of (Bu3Sn)2, and then treating the resulting atom-transfer 5-exo-cyclization product I with fluoride ion. The mechanistic studies showed that the kinetically favored 5-exo-cyclized radical C, formed from radical B, was trapped when the concentration of Bu3SnH was high enough to give E. At lower concentrations of Bu3SnH and higher reaction temperatures, radical C rearranged into the more stable ring-enlarged 4-oxa-3-silacyclohexyl radical D, which was then trapped with Bu3SnH to give F. The ring-enlarging rearrangement was experimentally proved to occur via a pentavalent-like silicon-bridging transition state X (Scheme 9). This radical reaction with a vinylsilyl tether has been successfully applied to the synthesis of biologically important 4'-branched-chain sugar nucleosides andC-glycosides.
A new method for synthesis of cycloalkane derivatives was explored. The new method involves the formation of cycloalkane derivative in a one-pot process using the anion of allyl phenyl sulfone and epoxymesylate. Total synthesis of marine oxylipin constanolactone E and bacillariolides I-IIIwas achieved applying this new method. Constanolactone E, isolated from the marine red alga Constantinea simplex, is a cyclopropanecontaining oxylipin. Reaction of the lithio derivative of allyl phenyl sulfone with chiral epoxymesylate gave cyclopropane derivative. Cyclopropane derivative was converted to alkyl sulfone, corresponding to C1-C9 segment. Aldehyde corresponding to C10-C20 segment was synthesized from 2-deoxy-D-ribose. Coupling reaction of two segments completed the total synthesis of constanolactone E. Bacillariolides I, II and III, isolated from the marine diatom, Pseado-nitzschia multiseries, are cyclopentane-containing structurally unique oxylipins. Reaction of the lithio derivative of allyl phenyl sulfone with epoxymesylate gave cyclopentane derivative. Cyclopentane derivative was converted to the aldehyde corresponding to C1-C8 segment. Coupling reaction of the aldehyde with Wittig reagent corresponding to C9-C20 segment completed the total synthesis of bacillariolide II. Bacillariolides I and III were synthesized from the cyclopentane derivative via epimerization of the C-7 position, respectively.
Recent remarkable progress in palladium and nickel-catalyzed reactions and its increasing impact on organic synthesis are surveyed. Aryl chlorides, which have been regarded as inactive compounds in nucleophilic substitutions, undergo facile Pd-catalyzed substitition. In these reactions of aryl chlorides, use of bulky and electron-rich ligands, typically tri (tert-butyl) phosphine, are important. Pd-catalyzed amination, Mizonoki-Heck reaction, Suzuki-Miyaura coupling, Sonogashira reaction, α-arylation of ketones with aryl chlorides proceed smoothly using various bulky and electron-rich ligands. Also active Pd catalysts are prepared by coordination of stable N-heterocyclic carbene ligands. Ni-phosphine complexes, impregnated on carbon were found to be very active catalysts for the substitution of aryl chlorides.